Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery

Area of Science:

• Endothelial cell biology
• Vascular inflammation
• Cell signaling

Background:

• Intracellular cyclic AMP (cAMP) inhibits endothelial cell permeability through protein kinase A (PKA)-dependent and -independent pathways.
• The role of PKA-independent cAMP pathways in intact microvessels remains understudied.

Purpose of the Study:

• To investigate the contribution of the cAMP-activated exchange protein activated by cAMP (Epac)/Rap1 pathway to the anti-inflammatory effects of cAMP in rat venular microvessels.
• To determine if Epac/Rap1 activation attenuates platelet-activating factor (PAF)-induced increases in microvessel permeability.

Main Methods:

• Utilized a cAMP analog (O-Me-cAMP) that specifically activates Epac/Rap1 without affecting PKA.
• Measured microvessel hydraulic conductivity (Lp) to quantify permeability changes.
• Assessed the localization and arrangement of vascular endothelial (VE)-cadherin using immunofluorescence.

Main Results:

• O-Me-cAMP significantly attenuated the PAF-induced increase in microvessel hydraulic conductivity.
• PAF caused a disruption in VE-cadherin organization, characterized by lateral spikes and breaks.
• O-Me-cAMP pretreatment prevented the PAF-induced VE-cadherin rearrangement.

Conclusions:

• The Epac/Rap1 pathway plays a significant role in stabilizing endothelial cell-cell adhesion.
• Epac/Rap1 activation contributes to the anti-permeability effects of cAMP in intact microvessels.
• Impaired Epac/Rap1 modulation of cell adhesion may underlie increased microvessel permeability during acute inflammation.